PROJECT SUMMARY The olfactory system is intimately connected with limbic brain regions that mediate memory. This connection may explain in part the power of familiar scents to call forth vivid episodic memories. For example, the smell of baking gingerbread might evoke the memory of a particular Christmas holiday. Given the substantial overlap between olfaction and memory, it is not surprising that odors have emerged as key players in targeted memory reactivation (TMR), a novel technique used to manipulate memory consolidation. During TMR, a memory task is learned in the presence of sensory cues (e.g. odors), and then the same cues are delivered during a subsequent period of sleep or wakefulness (i.e., reactivation). Reactivating memories during sleep often improves memory performance for the associated task, whereas reactivating memories during wake either has no effect or even worsens memory performance in some cases. Despite the fascinating behavioral consequences of TMR, the neural correlates are not well understood. That is, how do sensory cues, such as odors, mediate memory consolidation during TMR? Researchers speculate that sensory cues stimulate replay of associated memory traces, whereby memory-related neural activity is repeated to facilitate its integration into established cortical networks. However, there is no direct evidence that TMR evokes memory replay in the human brain. The overarching goal of the proposed research is to address this considerable gap in the literature by demonstrating odor-evoked memory replay in the human brain during olfactory TMR. To that end, I have designed a novel olfactory TMR paradigm optimized to investigate memory replay. In this paradigm, subjects will undergo visuospatial learning during functional magnetic resonance imaging (fMRI), and I will use multivariate methods to characterize ensemble patterns of neural activity that emerge over the course of learning. Then, subjects will continue to learn picture locations in the presence of olfactory cues. In a critical reactivation phase, I will deliver task-specific odors while subjects sleep (Aim #1) or lie awake (Aim #2) during fMRI scanning. Finally, I will assess visuospatial memory before and after reactivation. To test the hypothesis that odors trigger replay of associated memory traces during olfactory TMR, I will search for reemergence of learning-specific patterns of neural activity during reactivation. Moreover, I will compare neuroimaging and behavioral measures to characterize the relationship between neural replay and memory outcomes. By investigating the neural correlates of olfactory TMR during sleep and wakefulness, across both aims the proposed research will provide key insights into the mechanisms underpinning odor-mediated memory consolidation. Many neurological disorders are marked by memory deficits, and understanding the critical role of olfaction in manipulating memory consolidation could lead to the development of odor-based therapies.